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Purpose: Problems in management of oral cancers or precancers include identification of patients at risk for metastasis, tumor recurrence, and second primary tumors or risk for progression of precancers (dysplasia) to cancer. Thus, the objective of this study was to clarify the role of genomic aberrations in oral cancer progression and metastasis.Experimental Design: The spectrum of copy number alterations in oral dysplasia and squamous cell carcinomas (SCC) was determined by array comparative genomic hybridization. Associations with clinical characteristics were studied and results confirmed in an independent cohort.Results: The presence of one or more of the chromosomal aberrations +3q24-qter, -8pter-p23.1, +8q12-q24.2, and +20 distinguishes a major subgroup (70%–80% of lesions, termed 3q8pq20 subtype) from the remainder (20%–30% of lesions, non-3q8pq20). The 3q8pq20 subtype is associated with chromosomal instability and differential methylation in the most chromosomally unstable tumors. The two subtypes differ significantly in clinical outcome with risk for cervical (neck) lymph node metastasis almost exclusively associated with the 3q8pq20 subtype in two independent oral SCC cohorts.Conclusions: Two subtypes of oral lesions indicative of at least two pathways for oral cancer development were distinguished that differ in chromosomal instability and risk for metastasis, suggesting that +3q,–8p, +8q, and +20 constitute a biomarker with clinical utility for identifying patients at risk for metastasis. Moreover, although increased numbers of genomic alterations can be harbingers of progression to cancer, dysplastic lesions lacking copy number changes cannot be considered benign as they are potential precursors to non-3q8pq20 locally invasive, yet not metastatic oral SCC. Clin Cancer Res; 17(22); 7024–34. ©2011 AACR.

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Purpose: To identify mechanisms and mediators of resistance to antiangiogenic therapy in human glioblastoma. Experimental Design: We carried out microarray gene expression analysis and immunohistochemistry comparing 21 recurrent glioblastomas progressing during antiangiogenic treatment with VEGF neutralizing antibody bevacizumab to paired pretreatment tumors from the same patients. Results: Microarray analysis revealed that bevacizumab-resistant glioblastomas (BRG) had two clustering patterns defining subtypes that reflect radiographic growth patterns. Enhancing BRGs (EBRG) exhibited MRI enhancement, a long-established criterion for glioblastoma progression, and expressed mitogen-activated protein kinases, neural cell adhesion molecule-1 (NCAM-1), and aquaporin 4. Compared with their paired pretreatment tumors, EBRGs had unchanged vascularity and hypoxia, with increased proliferation. Nonenhancing BRGs (NBRG) exhibited minimal MRI enhancement but had FLAIR-bright expansion, a newer criterion for glioblastoma recurrence since the advent of antiangiogenic therapy, and expressed integrin α5, laminin, fibronectin1, and PDGFRβ. NBRGs had less vascularity, more hypoxia, and unchanged proliferation than their paired pretreatment tumors. Primary NBRG cells exhibited more stellate morphology with a 3-fold increased shape factor and were nearly 4-fold more invasive in Matrigel chambers than primary cells from EBRGs or bevacizumab-naive glioblastomas (P < 0.05). Conclusion: Using microarray analysis, we found two resistance patterns during antiangiogenic therapy with distinct molecular profiles and radiographic growth patterns. These studies provide valuable biologic insight into the resistance that has limited antiangiogenic therapy to date. Clin Cancer Res; 18(10); 2930–42. ©2012 AACR.

The biologic behavior of oral dysplasia (precancers) and squamous cell carcinoma (SCC) is unpredictable, the main problems in management being identification of patients at risk for metastasis or risk of progression of dysplasias to cancer. Neck metastasis, the most significant clinical factor causing death in oral SCC, reduces survival by 50%. We utilized array comparative genomic hybridization (CGH) to clarify the role of genomic aberrations in oral cancer progression and metastasis. Two oral SCC cohorts: cohort#1, n=89 (Snijders et al, 2005)) and cohort#2, n=63 (with associated pathologic nodal status and 5 year clinical follow up) were profiled using BAC CGH arrays. Two dysplasia cohorts, one with no association to cancer (cohort D1, n=29) and one associated with previous or subsequent cancer (cohort D2, n=10) were also profiled for recurrent copy number aberrations using array CGH. Associations with clinical characteristics were studied and results confirmed in an independent SCC cohort (cohort#3, n=14, Smeets et al., 2009). All samples used in this study were restricted to oral cavity sites only and were archival formalin fixed paraffin embedded tissue. Copy number alterations distinguished two oral dysplasia and cancer subtypes. The presence of one or more of the chromosomal aberrations +3q24-qter, -8pter-p23.1, +8q12-q24.2, and +20 distinguished a major subgroup (70%-80% of lesions, termed 3q8pq20 subtype) from the remainder (20%-30% of lesions, non-3q8pq20). Most notably, 3q8pq20 and non-3q8pq20 subtypes differed significantly in clinical outcome with risk for cervical (neck) lymph node metastasis almost exclusively associated with the 3q8pq20 subtype in two independent oral SCC cohorts (cohort#2 and cohort#3). As metastasis to the cervical lymph nodes is a major determinant of survival in oral SCC patients, our findings indicate that chromosomal aberrations +3p, -8p, +8q and +20 provide a potential biomarker to identify patients at no or low risk of metastasis. The negative predictive value (NPV) i.e. the ability to predict N0 cases at biopsy was 93% for cohort#2 and 100% in cohort#3. Currently, almost all patients diagnosed with oral SCC are treated with comprehensive neck dissection at the time of tumor resection, as salvage of patients who subsequently develop neck metastasis is poor. We propose that the +3q, -8p, +8q and +20 signature is suitable for stratifying patients for risk of metastasis prior to surgery, and so can guide surgical treatment for one of the most challenging treatment decisions - how to treat patients with clinically node-negative (N0) necks. Identification of patients with low risk for metastasis would spare them additional major surgery with its risks and morbidity, as well as reduce medical costs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5079. doi:1538-7445.AM2012-5079

The 5-year survival rate for oral squamous cell carcinoma (SCC) patients at 40% has not improved over the past 40 years. Since genomes of 75-80% of oral SCCs are characterized by regions of gains and losses, we investigated whether copy number aberrations could be used to address two important problems in oral cancer management - identification of (a) tumors with metastatic potential and (b) dysplastic lesions at risk for progression to cancer. Neck metastasis, the most significant clinical factor responsible for death from oral cancer reduces survival by 50%. To determine if copy number aberrations would distinguish tumors with metastatic potential, we carried out array comparative genomic hybridization (CGH) on 26 N0 and 38 N+ cases with at least 5-year follow up (diagnosed between 1997 and 2005). In order to reduce the multiple testing correction, regions of recurrent aberration were identified in an independent set of 89 oral SCCs (Snijders et al. 2005). A comparison of the frequency of aberrations affecting these regions in the N0 and N+ cases revealed no significant differences between the N0 and N+ cases after correction for multiple testing. We used a similar approach to determine if there are significant copy number differences between oral dysplasia and oral SCC. Most oral SCCs are preceded by precancerous lesions, characterized by varying degrees of dysplasia (graded from mild to severe). Transformation to oral SCC is associated with 16% of mild and 55% of moderate/severe dysplasia. Copy number profiles for 44 dysplasia samples comprised of approximately equal numbers of cases graded mild, moderate or severe were obtained by array CGH. Although fewer copy number changes were observed in dysplasia compared to SCC, gains of 3q, 8q and/or chromosome 20 were present at approximately equal frequencies in dysplasia and SCC. In addition, the rare narrow amplicons, characteristic of oral SCC (Snijders et al. 2005), were present in dysplasia. To identify copy number alterations distinguishing dysplasia and SCC, regions of recurrent aberration were defined in an independent set of oral SCCs (the 64 cases from the metastasis study described above). The frequency of these copy number alterations was compared between the dysplasia and the 89 SCC cases (Snijders et al. 2005). Gain of 7p, including EGFR in SCC was found to be significant after correction for multiple testing. This observation is consistent with previous reports of increased expression of EGFR with progression of dysplasia to cancer (Garnis et al., 1998). Since 20-25% of oral SCC harbor almost no copy number changes, suggesting that dysplasia lacking copy number changes may have potential to progress to SCC with chromosomally stable genomes, we suggest that measurement of EGFR expression and/or other genes on 7p may provide a more effective biomarker for dysplasia progression than 7p copy number. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2137.